Genotoxicity of nano/microparticles in in vitro micronuclei, in vivo comet and mutation assay systems

<p>Abstract</p> <p>Background</p> <p>Recently, manufactured nano/microparticles such as fullerenes (C₆₀), carbon black (CB) and ceramic fiber are being widely used because of their desirable properties in industrial, medical and cosmetic fields. However, there are few data on these particles in mammalian mutagenesis and carcinogenesis. To examine genotoxic effects by C₆₀, CB and kaolin, an <it>in vitro </it>micronuclei (MN) test was conducted with human lung cancer cell line, A549 cells. In addition, DNA damage and mutations were analyzed by <it>in vivo </it>assay systems using male C57BL/6J or <it>gpt </it>delta transgenic mice which were intratracheally instilled with single or multiple doses of 0.2 mg per animal of particles.</p> <p>Results</p> <p>In <it>in vitro </it>genotoxic analysis, increased MN frequencies were observed in A549 cells treated with C₆₀, CB and kaolin in a dose-dependent manner. These three nano/microparticles also induced DNA damage in the lungs of C57BL/6J mice measured by comet assay. Moreover, single or multiple instillations of C₆₀and kaolin, increased either or both of <it>gpt </it>and Spi^-mutant frequencies in the lungs of <it>gpt </it>delta transgenic mice. Mutation spectra analysis showed transversions were predominant, and more than 60% of the base substitutions occurred at G:C base pairs in the <it>gpt </it>genes. The G:C to C:G transversion was commonly increased by these particle instillations.</p> <p>Conclusion</p> <p>Manufactured nano/microparticles, CB, C₆₀and kaolin, were shown to be genotoxic in <it>in vitro </it>and <it>in vivo </it>assay systems.</p

環境汚染物質による突然変異誘発の分子構造: 3-ニトロベンズアントロン、クロトンアルデヒド、アクロレインを対象として

本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものである京都大学0048新制・課程博士博士(工学)甲第7521号工博第1762号新制||工||1124(附属図書館)UT51-98-W265京都大学大学院工学研究科環境地球工学専攻(主査)教授 松井 三郎, 教授 森澤 眞輔, 教授 齋藤 烈学位規則第4条第1項該当Doctor of EngineeringKyoto UniversityDFA

Modulation of benzo[a]pyrene–DNA adduct formation by CYP1 inducer and inhibitor

Abstract Benzo[a]pyrene (BaP) is a well-studied pro-carcinogen that is metabolically activated by cytochrome P450 enzymes. Cytochrome P4501A1 (CYP1A1) has been considered to play a central role in the activation step, which is essential for the formation of DNA adducts. This enzyme is strongly induced by many different chemical agents, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which binds to the aryl hydrocarbon receptor (AhR). Therefore, AhR activators are suspected to have the potential to aggravate the toxicity of BaP through the induction of CYP1A1. Besides, CYP1A1 inhibitors, including its substrates, are estimated to have preventive effects against BaP toxicity. However, strangely, increased hepatic BaP–DNA adduct levels have been reported in Cyp1a1 knockout mice. Moreover, numerous reports describe that concomitant treatment of AhR activators reduced BaP–DNA adduct formation. In an experiment using several human cell lines, TCDD had diverse modulatory effects on BaP–DNA adducts, both enhancing and inhibiting their formation. In this review, we focus on the factors that could influence the BaP–DNA adduct formation. To interpret these complicated outcomes, we propose a hypothesis that CYP1A1 is a key enzyme for both generation and reduction of (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), the major carcinogenic intermediate of BaP. Conversely, CYP1B1 is thought to contribute only to the metabolic activation of BaP related to carcinogenesis

The 30th summer school of the Research Community for Mechanisms of Mutations

Abstract The 30th summer school of the Research Community for Mechanisms of Mutations was held on September 2nd-3rd, 2017 at the Kyoto Prefecture Seminar House. The Community celebrated the 30th anniversary of the school this year. The Community has been organizing a meeting once a year since it was founded as the Society for Mechanisms of Anti-mutagenesis and Anti-carcinogenesis Studies in 1987. The Society was reorganized to the current Community in 2006, and since then has a summer school aimed at providing information on mutation research frontiers and exchanging scientific information among young scientists such as graduate students, post-doctoral fellows, and assistant professors. This year, three eminent scientists were invited to discuss radiation cluster damage, the evolution of snake venom, and colibactin and colorectal cancer, while 15 participants presented their own research. Fifty-six participants joined in enthusiastic discussions and acquired new scientific knowledge